Note: Descriptions are shown in the official language in which they were submitted.
~l~5~ 54
AG-1217
2-AMINO-4-SUBSTITUTED-5-THIAZOLECARBOXYLIC
ACIDS AND THEIR DERIVATIVES
This invention relates to novel 2-amino-4-
substituted -5-thiazolecarboxylic acids and derivatives
thereof which are intermediates for the preparation of
2,4,5-substituted thiazoles which are effective
herbicidal safening agents.
BACKGROUND OF THE INVENTION
Herbicides are very useful for controlling
certain weeds in the presence of growing crops. However,
many herbicides injure certain crop plants slowing growth
and development at rates necessary to kill or stunt weeds.
Accordingly, some herbicides cannot be used for control-
ling weeds in the presence of certain crops. Obviously,
a safening agent which consists of a chemical compound
that is to be used to treat either the seed of the crop
plant, the crop plant locus, or the crop plant itself,
to reduce the injury due to application of a herbicide
without a corresponding reduction of herbicidal action
on weeds, is quite beneficial. The compounds of the
present invention can be used to prepare certain 2-
substituted-4-substituted-5-thiazolecarboxylic acids and
derivatives thereof, which are effective herbicidal
safeners. U. S. Patent 4,199,506 describes such 2,4-
disubstituted-5-thiazolecarboxylic acids and derivatives
thereof as well as their use as safening agents.
.~ ~
l6~4
-2- AG 1217
DESCRIPTION OF THE INVENTION
The present invention relates to compounds
having the formula:
o
R - C = C - C - () nR
N S
~ /
C
NH2
wherein n is zero or one; R is selected from the group
consisting of alkyl having 3 to 9 carbon atoms, cycloalkyl
having 3 to 8 carbon atoms, halo(lower)alkyl,
and
z
~Y
ïO Y and Z are independently selected from the group
consisting of hydrogen, halogen, trifluoromethyl and lower
alkyl; when n is one, Rl is selected from the group
consisting of hydrogen, alkyl having 1 to 10 carbon atoms,
lower alkenyl, lower alkynyl, lower alkoxy lower alkyl,
halo~lower)alkyl, benzyl, phenyl and phenyl substituted by
one or two members selected from the group consisting of
halogen, lower alkyl and trifluoromethyl; when n is zero,
R is -NR2R3 where R2 and R3 are independently equal to
lower alkyl; provided that when n is one and R is
hydrogen, Z and Y cannot both equal hydrogen; further
provided that when Rl is alkyl containing l to 10 carbon
atoms or benzyl, R cannot equal trifluoromethyl.
As used herein, the terms "lower alkyl", "lower
alkoxy", "lower alkenyl" and "lower alkynyl" are
understood to include alkyl, alkoxy, alkenyl and alkynyl
groups having up to five carbon atoms, inclusive.
The terms "alkyl", "alkoxy", "alkenyl" and
"alkynyl" are understood to include branched and
unbranched groups. When Rl is lower alkenyl, allyl is
preferred. When Rl is lower alkynyl, propargyl is
~S~654
-3- AG-1217
preferred~
"Halogen" includes bromine, chlorine, fluorine
and iodine.
"Cycloalkyl" containing 3 to 8 compounds
includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl and cyclooctyl. Preferred for use herein are
those cycloalkyls containing 5 to 7 carbon atoms,
cyclohexyl is most preferred.
The term "halo(lower)alkyl" is understood to
mean those alkyl moieties having up ~o five carbon atoms
wherein at least one hydrogen atom has been replaced by a
halogen atom. Specifically included are those alkyl
moieties in which all of the hydrogen atoms have beèn
replaced by halogen atoms, such as trifluoromethyl.
The following may be mentioned as examples of
the 2-amino-4-substituted-5-thiazolecarboxylate which are
valuable as intermediates in the preparation of herbicidal
antidotes:
ethyl 2-amino-4-isopropyl-5-thiazolecarboxylate,
propyl 2-amino-4-ethyl-5-thiazolecarboxylate,
ethyl 2-amino-4-t-butyl-5-thiazolecarboxylate,
ethyl 2-amino-4-(p-fluorophenyl)-5-thiazolecarboxylate,
ethyl 2-amino-4-(p-chlorophenyl)-5-thiazolecarboxylate,
ethyl 2-amino-4-(o-chlorophenyl)-5-thiazolecarboxylate,
ethyl 2-amino-4-(m-tolyl)-5-thiazolecarboxylate,
ethyl 2-amino-4- ~,Oc,~-trifluoro-m-tolyl)-5-thiazole-
carboxylate,
ethyl 2-amino-4-cyclohexyl-5-thiazolecarboxylate,
2,2,2-trichloroethyl 2-amino-4-trifluoromethyl-5-thiazole-
carboxylate,
2-butoxyethyl 2-amino-4-trifluoromethyl-5-thiazole-
carboxylate,
phenyl 2-amino-4-trifluoromethyl-5-thiazolecarboxylate,
p-chlorophenyl 2-amino-4-trifluoromethyl-5-thiazole-
carboxylate,
propargyl 2-amino-4-trifluoromethyl-5-thiazolecarboxylate,
allyl 2-amino-4-trifluoromethyl-5-thiazolecarboxylate,
~5~S~
-~- AG-1217
N,N-diethyl-2-amino-4-trifuloromethyl-5-thiazole-
carboxamide,
N,N-diethyl-2-amino-4-isopropyl-5-thiazolecarboxamide and
N,N-diethyl-2-amino-4-chloromethyl-5-thiazolecarboxamide.
The 2-amino-4-substituted-5-thiazolecarboxylic
acids and derivatives of the foregoing formula may be pre-
pared utilizing the following procedures. For purposes of
clarification, these procedures are summarized by
Schemes I and II.
Compounds of the present invention wherein n is
equal to one are prepared according to Scheme I.
- C - CH2 - C - ORl S2C12 R - C - CH - C - O
.. .. .. .
O O o Cl O
S o
~2N - CNH R - C = C - C - oRl (I)
N S
C
NH2
In accordance with the above reaction scheme, ketoesters
in chloroform are added dropwise to one equivalent of
sulfuryl chloride. The reaction mixture is held at reflux
for a number of hours and the chloroform removed under
reduced pressure. An equimolar portion of the resultant
2-chloro-3-ketoester is added to thiourea in ethanol and
held at reflux for 15-20 hours. Ethanol is then removed
under reduced pressure and the residue neutralized with
sodium bicarbonate solution to give 2-amino-4-substituted-
5-thiazolecarboxylic acids or esters.
The preparation of compounds of the present
invention wherein n is equal to zero and Rl is equal to
-NR2R3 is illustrated by Scheme II:
~lS~54
-5- ~G-1217
O O
HNR2R3~ R - C = C - C - NR2R3
N S tl S
C C
lH2 NH2
(R = Cl_10 alkyl)
(II)
Further details of the compounds of the present
invention and tlleir preparation are found in the following
non-limiting examples.
Exam~le 1
Preparation of EthYl 2-Amino-4-Ethyl-5-Thiazole-
carboxylate. Ethyl 2-chloro-3-oxo-pentanoate was prepared
from ethyl 3-oxo-pentanoate and sulfuryl chloride
utilizing the procedure of Bankowski et al, Rocz. Chem.,
Volume 49, Page 1899 (1971). A mixture of 9.2 9 (0.0515
mole) of ethyl 2-chloro-3-oxo-pentanoate, 3.92 g (0.0515
mole) of thiourea and 30 ml. of ethanol was held at reflux
for 17 hours. Ethanol was removed under reduced pressure
and the residue was treated with 300 ml. of saturated
sodium bicarbonate solution~ The solid precipitate was
collected to give 11.2 g of white solid, m.p. 165-170C.
which was recrystallized from ethanol to give 7.7 g (75%)
of ethyl 2-amino-4-ethyl-5-thiazolecarboxylate as
colorless prisms, m.p. 177-179C.
Anal. Calc'd.for C8H12N2O2S: C, 47.97; H, 6.04; N, 13.99;
Found: C, 47.92; H, 6.04; N, 14.00.
Example 2
Preparat on of Ethyl 2-Amino-4-t-Butyl-5-Thia-
zolecarboxylate. Utilizing ethyl 2-chloro-4,4-dimethyl-
3-oxo-pentanoate and the procedure of Example 1, ethyl
2-amino-4-t-butyl-5-thiazolecarboxylate was prepared, m.p.
99.0-1oo.0c.
Anal. Calc'd. for CloH16N2O2S: C, 52.60; H~ ;
Found: C, 52.56; H, 7.06; N, 12.21
iS~
-6- .~G-1217
Example 3
Preparation of E~yl 2-Amino-4-(p-Fluorophenyl)-
5-Thiazolecarboxylate. A mixture of 10.5 g (0.05 mole) of
ethyl ~-fluorobenzoylacetate, 6.7 g (0.05 mole) of
sulfuryl chloride and 30 ml. of chloroform was held at
reflux for 18 hours and cooled. The chloroform solution
was washed with water, dried (l~gS04) and concentrated
under reduced pressure. The residue was distilled to give
10.8 g (88~) of ethyl 2-chloro-(~-fluoro)-benzoylacetate
as an oil. A mixture of 10.8 g tO.0441 mole) of ethyl
2-chloro-(E-fluoro)-benzoylacetate, 3.36 g (0.0441 mole)
of thiourea, 20 ml. of water and 10 ml. of ethanol was
held at reflux for 3 hours. Ethanol was removed under
reduced pressure. The residue was made basic with
saturated sodium bicarbonate. The solid was filtered,
washed with water and recrystallized from ethanol to give
8.9 g (76%) of ethyl 2-amino-4-tp-fluorophenyl)-5-
thiazolecarboxylate as white prisms, m.p. 205-208C.
Anal. Calc'd for C12HllFN202S: C, 54.11; H, 4.16; N, 10.52
Found: C, 54.12; H, 4.16; N, 10.52
Example 4
Preparation of Ethyl 2-Amino-4-p-Chlorophenyl-5-
Thiazolecarboxylate. To a cold (SC) vigorously stirred
mixture of 121.87 g (0.936 mole) of ethyl acetoacetate,
314 ml. of benzene and 62~ ml. of water was added 41.25
ml. of 33% sodium hydroxide. To the above mixture was
added simultaneously, in two dropping funnels, 177.0 g
(1.01 mole) of p-chlorobenzoyl chloride and 188.8 ml. of
33~ sodium hydroxide in 2 hours. The reaction mixture
became pasty. The reaction mixture was heated at 35C.
for 1 hour, cooled and filtered to give 170.0 g of sodium
salt of ethyl 2-benzoylacetoacetate. Part (150 g) of this
salt was added to a mixture of 39.0 9 (0.729 mole) of
ammonium chloride and 78 ml. of concentrated ammonium
hydroxide in 780 ml. of water. The mixture was stirred at
40-50C. for 3 hours and cooled in an ice bath. The
precipitate was filtered to give 115.5 g of yellow solid
which was Kugelrohr distilled to give 76.0 g (38~ based on
~1S ~54
-7- AG-1217
ethyl acetoacetate) of crude ethyl ~-chlorobenzoylacetate.
mixture of 40.0 g (0.175 mole) of crude ethyl
~-chlorobenzoylacetate, 24.2 g (0.18 mole) of sulfuryl
chloride and some chloroform was held at reflux for ~
hours, cooled and concentrated to give 49.0 g of crude
ethyl 2-chloro-~-chlorobenzoylacetate. A mixture of 46.0
g (0.174 mole) of crude ethyl 2-chloro-p-chlorobenzoyl-
acetate, 13.25 9 (0.174 mole) of thiourea, and 174 ml. of
ethanol was held at reflux for ~ hours and cooled. The
precipitate was filtered and neutralized with saturated
sodium bicarbonate. The insoluble material was filtered
to give 37.0 9 (80%) of ethyl 2-amino-4-E-chlorophenyl-5-
thiazolecarboxylate, m.p. 198-200C.
Anal. Calc'd for C12HllClN202S: C, 50.96; H, 3.92;
N, 9.90;
Found: C, 50.88; ~, 3.93;
N, 9.90.
Example 5
Preparation of Ethyl 2-Amino-4-(o-Chlorophenyl)-
5-Thiazolecarboxylate. To a cold (5C.) mixture of 55.0 g
(0.423 mole) of ethyl acetoacetate, 70 ml. of benzene,
18.3 ml. of 33% sodium hydroxide, and 141 ml. of water was
added simultaneously with vigorous stirring 80.0 g (0.457
mole) of o-chlorobenzoyl chloride and 7~ ml. of 33~ sodium
hydroxide in 1 hour. The aqueous solution of the sodium
salt of ethyl o-chlorobenzoylacetoacetate was stirred with
22.5 g (0.424 mole) of ammonium chloride ~or 18 hours.
The aqueous solution was then saturated with 25.0 g of
sodium chloride. At this moment, some precipitate formed
which was filtered. The analysis indicated this material
was mainly the sodium salt of ethyl o-chlorobenzoylaceto-
acetate. The sodium salt and the aqueous filtrate were
combined and acidified with dilute hydrochloric acid. The
oil which separated was extracted with ether. The ether
solution was dried (MgSO4) and concentrated under reduced
pressure. The residue was ICugelrohr distilled to give
30.0 g of oil which contained mainly ethyl o-chloro-
benzoylacetoace~ate. This material was stirred with a
~s~j5~
8- AG-1217
mixture of 7.2 g of ammonium chloride, 14 ml. of
concentrated ammonium hydroxide and 150 ml. of water and
worked up as described in Example 4 to give 16.6 g (15~)
of crude ethyl o-chlorobenzoylacetate which was about 92~
pure. A mixture of 15.0 g (0.055 mole) of ethyl o-chloro-
benzoylacetate, 9.5 (0.070 mole) of sulfuryl chloride and
20 ml. of chloroform was held at reflux for 6 hours and
concentrated to give 17.3 g of crude ethyl 2-chloro-o-
chlorobenzoylacetate. A mixture of 17.0 g (0.065 mole) of
ethyl 2-chloro-o-chlorobenzoylacetate, 4.94 g ~0.065 mole)
of thiourea and 65 ml. of ethanol was held at reflux for 2
hours and worked up as described in Exarnple 4 to give lS.O
g of solid, m.p. 114-135C. which was recrystallized twice
from ethanol to give 5.8 g (31%) of ethyl 2-amino-4-
to-chlorophenyl)-S-thiazolecarboxylate, m.p. 165-166C.
Anal. Calc'd for C12HllClN202S: C, 50.96; H, 3.92;
N, 9.90; Cl, 12.54.
Found: C, 50.96; H, 3.96;
N, 9.91; Cl, 12.54.
Example 6
Preparation of Ethyl 2-Amino-4-(m-Tolyl)-S-
Thiazolecarboxylate. To a cold (5C.) mixture o~ 137.5 g
(l.OS mole) of ethyl acetoacetate, 175 ml. of benzene, 325
ml. of water, and 45.~ ml. of 33~ sodium hydroxide was
added simultaneously 221.05 g (1.430 mole) of m-toluoyl
chloride and 190 ml. of 33~ sodium hydroxide as described
in Example 4. The aqueous solution of sodium salt of
ethyl _-toluoylacetoacetate was stirred with 56.3 g of
ammonium chloride overnight and worked up as described in
Example 4 to ~ive 38.0 g (17%) of crude ethyl m-toluoyl-
acetate after a Kugelrohr distillation (95-98C. at 0.05
mm Hg). A ~ixture of 20.5 g (0.1 mole) of crude ethyl
m-toluoylacetate, 13.6 g (0.105 mole) of sulfuryl
chloride, and 30 ml. of chloroform was held at reflux for
6 hours and worked up as described in Example 4 to give
25.0 g of ethyl 2-chloro-m-toluoylacetate, which was used
directly as described below. A mixture of 22.5 g (0.1
mole) of ethyl 2-chloro-m-toluoylacetate, 7.5 g (0.11
s~
-9_ ~G-1217
mole) of thiourea and 100 ml. of ethanol was held at
reflux for 2 hours and worked up as described in Example 4
to give 23.0 g of solid, which was recrystallized from
ethanol to give 11.6 g (44~6) of ethyl
2-amino-4- (m-tolyl~-5-thiazole-
carboxylate, m.p. 185-187C.
Anal. Calc'd. forC13H14N202S: ,
N, 10.58.
Found: C, 59.55; H, 5.42;
N, 10.68.
Example 7
Preparation of Ethyl 2-Amino-4-Isopropyl-5-
Thiazolecarboxylate. Utilizing the procedure of Example
1, a mixture of 1.97 g (0.01 mol) of ethyl 2-chloro-4-
methyl-pentanoate, 0.75 g (0.01 mol) of thiourea and 30 ml
of ethanol was held at reflux for 18 hours. Ethanol was
removed under reduced pressure. The residue was
crystallized from hexane. The solid precipitates were
dissolved in ether. The ether solution was washed with
water, dried over magnesium sulfate and concentrated under
reduced pressure. The residue was recrystallized from
benzene-ether to give 0.85 g (39.6%) of ethyl 2-amino-4-
isopropyl-5-thiazolecarboxylate, m.p. 173-176C.
Anal. Calc'd. for CgH14N202S: C, 50. 44; H, G. 58; N, 6.58;
Found: C, 50.47; H, 6.61; N, 13.07.
~S~5~
AG-12]7 -~
--10--
Example 8
Preparation_of Ethyl 2-Chloro-4-Isopropyl-5
Thiazolecarboxylate.
_ __
To a well stirred mixture of 12.36 g (0.12 mol)
of _-butyl nitrite, 12.90 g (0.0963 mol) of CuC12 and ---
320 ml of ace~onitrile was added portionwise 16.7 g
(0.078 mol) of ethyl 2-amino-4-isopropyl-5-thiazole- -
carboxylate in 40 minutes time. The reaction mixture ---
was stirred at room temperature for 1 hour and then
heated to 65C. The reaction mixture was filtered and
the filtrate was poured into 400 ml of 6N HCl. The
aqueous mixture was extracted with ether. The ether
extracts were dried (MgSO4) and concentrated to give 17.0 -
g of oil which was kugelrohr distilled at 1.5 mm to give
15.7 g (86~) of ethyl-2-chloro-4-isopropyl-5-thiazole- --
carboxylate, nD5 = 1.5145.
Anal. Calc'd for CgH12ClNO2S: C, 46.24; H, 5.18; N, 5.99. -
Found: C, 46.40; H, 5.22; N, 6.06.
Example 9
.
Preparation of Ethyl 2-Chloro-4-t-Butyl-5-Thia-
::
zolecarboxylate.
To a well stirred mixture of 38.62 g (0.375 mol) :
of t-butylnitrite, 43.3 g (0.3 mol) of CuC12 and 300 ml
of acetonitrite was added 57.0 g (0.25 mol) of ethyl 2- -
amino-4-t-butyl-5-thiazolecarboxylate in one hour. The
reaction mixture was worked up as described in Example 8
to give 55.9 g of crude oil which was distilled at 1 mm to
give first fraction, 4.4 g, b.p. 90C, nD5 1.5008, and
second fraction, 47.6 g (79%), b.p. 110C,nD5 1.5160, -
identified as 2-chloro-4-t-butyl-5-thiazolecarboxylate.
Anal. Calc'd for CloH14ClNO2S: C, 48.48; H, 5.70; N, 5.56. -
Found: C, 48.41; H, 5.73; N, 5.62.
~5~6S~
-11- AG-1217
xample 10
Preparat_on of Ethyl 2-Chloro-_-p-Chlorophenyl-
5-Thiazolecarboxylate.
To a well stirred mixture of 14.6 g (0.142 mol)
t-butylnitrite 15.3 g (0.113 mol) of cupric chloride and --
100 ml of dry acetonitrile was added 24.75 g (0.0875 mol) -
of ethyl 2-amino-4-p-chlorophenyl-5-thiazolecarboxylate -
in 30 minutes. The reaction mixture was controlled below
45~C with an ice-water bath. The reaction mixture was
stirred for 10 minutes and filtered. The insoluble -
material was washed with diluted HCl and recrystallized --
from ethanol-chloroform to give 14.1 g of white solid
m.p. 117-119C which was kugelrohr distilled at 1 mm to -
give 13.8 g of ethyl 2-chloro-4-p-chlorophenyl-5-thiazole-
carboxylate, m.p. 120-121.5C. The original acetonitrile
filtrate was poured into 20~ HCl and the precipitate was
collected and kugelrohr distilled at 1 mm to give 7.0 g
of white solid which was stirred with hexane-chloroform
and filtered to give additional 4.7 g of final product,
total yield 70%. -~
Anal. Calc'd for C12HgC12NO2S: C, 47.70; H, 3.00; N, 4.64.
Found: C, 47.71; H, 2.97; N, 4.55.
In accordance with the procedure described in
Examples 8-10, the following compounds may be prepared,
as shown in Table I.
~ ¦ ~ I I ~ ~ I r I u~
~ F~ ~ ,~ r~
h rd
a) _ ~ ~1 , , , ", I ~ I
P~ r- I I . . I I I . I
,~ c~ o co ~ o ~ ~ o u~
Z ~ o o~
~i h Ln
h
a~ ~ ~ In ~ In Lr~ ~D O 1
,~ ~ o ~ o u~
r~ CO l~ ~ ~ I~ ~ a~ o
~i o ,~ o ,;
$1~ ~0 GO ~D ~r ~D O~ ~ N U')
U r~ O r-i O r~l r~l ~) ~ t~
~ ~ r~ r- r~ o ~ co
rrd- ~ ~ ~ O Ci~ I
1~ O 1~ n o ui o c~
r_) ~ ~ r~l ~ ~ ~ Lr~~n u~ u)In
~ .
O - ~ 'd
u _ ~ o rx) ~ ~r r~ r~,~
S~ V o co ~ ~ a~ r ~ o
H r~ ~ rn ~ ~~i 1~ O u~ o ~ u~
;~ C~)~z~
u~ u~ r~l rn ~J) r,q rn
P:; ~ ~ rn v~ O r.~l r~l r~l rn rn ~ r~
N 0N Z~ O ~ ~0
r
C) rJu~ r
r~ ~ Ln
o
N r~
ON a~
~DLn r~ ,~ ~D
u~ ~ ~ I I r~ r~ I I I I
NcP ~r~r I I Lr') ~ I I I IU~
r-ir-i r-i r-l r_l
r-l X~ ~ O ~ ~CNXt~
~N ~ r~
E4 ~r7
D
~I N rr1 ~rLn ~ t- r~ o
1151654 3 ~ ~ ~ ~ ~ ~ ~ ~ ~ r~
i54
-13-
Co~pounds of the present invention which are
prepared according to the procedure described in Scheme II
which may be mentioned, include, but are not li~ited to:
N,N-diethyl 2-am1no-4-trifluoromethyl-5-thiazole-
carboxamide,
N,N-diisopropyl-2-amino~4-isopropyl-5-thiazolecarboxamide,
N,N-di-tert-butyl-2-amino-4-phenyl-5-thiazolecarboxamide,
N,N-diethyl-2-amino-4-cyclohexyl-5-thiazolecarboxamide,
N,N-dipropyl-2-amino-4-chloromethyl-5-thiazolecarboxamide,
and N,N-di-n-butyl-4-trimethoXymethyl-5-thiazole-
carboxamide~
In accordance with the novel aspects of the
present invention, the 2-amino-4-substituted-thiazole-
carboxylates are intermediates in the preparation of
certain 2-substituted-4-substituted-
thiazole carboxylates which have been found to be
effective in reducing herbicidal injury to selected crop
plants due to application of herbicides.
Safening agents having the formula
o
R - C = C - C - (O)nR
N S
~ /
C
X
where R and Rl have the meanings previously described and
where X is equal to chloro, bromo, fluoro or iodo, may be
prepared utilizing compounds cf the present invention
according to the following procedure:
O O
., . ~.
R - C = C - C - (O)nR 1) NaNO2,HX R - C = C - C - (O)nR
2) CuX or KI~ l I
N S X = Cl, Br N S
C or I C
. ' ~III)
NH2 X
~5~ ~iS~
-14-
In accordance with the above reaction scheme, a
solution of the 2-aminothiazole compounds of the present
invention is diazotized at -50 to 30~ with sodium
nitrite. The resulting diazonium salt solution is poured
into an appropriate cuprous halide or potassium iodide
solution. After gas evolution has subsided, the reaction
mixture is extracted with ether. The eth2r extract is
dried, concentrated and the residue purified by l~ugelrohr
distillation at reduced pressure or by chromatography.
In yet another aspect of the present invention,
safening agents of the formula
~S~5~
-15- ~G-1217
R - C = C - C - o
S
C
Cl
where R and Rl are as previously described, and may be
prepared as illustrated in Scheme IV:
O O
R - C = C - C - ORl R - C = C - C - O
' ' t-BuONO,CuCl
N S (~H CN 2 ` N S
3 ~ /
C C
2 Cl (IV)
In accordance with the process illustrated by
the above reaction, to an equimolar mixture of t-butyl
nitrite and cupric chloride in acetonitrile is added an
approximately equimolar amount of the 2-aminothiazole
starting material. The reactants are usually admixed at
room temperature, i.e., about 25C. However, higher or
lower temperatures can be employed, the temperature not
being critical.
The separation of the resulting reaction product
from the reaction mixture is readily accomplished by
conventional means. For example, the reaction mixture may
be filtered to directly obtain the product or the filtrate
may be triturated with a suitable volume of 6N HCl.
Thereafter, the mixture is extracted with a suitable
organic solvent, as for example, ether. The extract is
dried and concentrated by Kugelrohr distillation.
Although this invention has been described with
respect to specific modifications, the details thereof
are not to be construed as limitations, for it will be
-16-
S~
apparent that various equivalents, changes and
modifications may be resorted to without departing Erom
the spirit and scope thereof and it is understood that
such equivalent embodiments ~re intended to be included
herein.
